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Handley, A et al. (2019) International Worm Meeting "ETS-5 regulates BAG-specific insulin signalling to control intestinal metabolism."

Handley, A, Wu, Q, Pocock, R, Sherry, T

[

International Worm Meeting,

2019]

Metabolic homeostasis is essential to life. The nervous system is the master metabolic coordinator that integrates input information such as external nutrient availability, levels of internal nutrient stores, and even past experiences. The outputs from the nervous system include changing food consumption, storing excess energy and nutrients, deciding what that excess should be stored as, and ultimately altering behaviour. Using Caenorhabditis elegans as a model - we investigate how gene-regulatory mechanisms in the nervous system control organismal metabolism and behaviour. We recently discovered that the conserved transcription factor ETS-5/Pet1, acts from the BAG and ASG neurons to control intestinal fat levels and exploration behaviour. Precisely how ETS-5 functions in the nervous system to affect intestinal fat levels is unknown. However, we have shown that neuropeptide secretion from the BAG neurons is an important factor in this pathway. We hypothesised that ETS-5 transcriptionally regulates neuropeptide expression in the BAG neurons, and that these BAG-specific neuropeptides in turn regulate intestinal metabolism. To test this hypothesis, we screened BAG-expressed neuropeptides for exploration defects and identified INS-1. Although INS-1 is expressed in multiple neurons, we show that INS-1 expressed specifically in the BAG neurons regulates intestinal fat levels and exploration behaviour. Our subsequent analysis revealed that ETS-5 directly binds to, and regulates the ins-1 promoter in the BAG neurons. This regulatory mechanism prevents fat storage and promotes exploration. Intriguingly, we found that excess nutrients in the intestine can reduce both ETS-5 and INS-1 levels within the BAG neurons, revealing a nutrient-dependent feedback loop. Together, this work reveals a neuron-intestinal signalling circuit that is critical for maintaining metabolic homeostasis.

Handley A et al. (2022) PLoS Biol "Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism."

Wu Q, Pocock R, Sherry T, Handley A, Cornell R

[

PLoS Biol,

2022]

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.

Sherry T et al. (2020) Development "Harmonization of L1CAM expression facilitates axon outgrowth and guidance of a motor neuron."

Pocock R, Sherry T, Nicholas HR, Handley A

[

Development,

2020]

Brain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. The Caenorhabditis elegans SMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-Terminal Binding Protein-1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon guidance by repressing the expression of SAX-7 - a L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial as deregulated SAX-7/L1CAM causes severely aberrant SMD axons. We found that axonal defects caused by deregulated SAX-7/L1CAM are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.

Godini R et al. (2021) Front Neurosci "Transcription Factors That Control Behavior-Lessons From C. elegans."

Handley A, Godini R, Pocock R

[

Front Neurosci,

2021]

Behavior encompasses the physical and chemical response to external and internal stimuli. Neurons, each with their own specific molecular identities, act in concert to perceive and relay these stimuli to drive behavior. Generating behavioral responses requires neurons that have the correct morphological, synaptic, and molecular identities. Transcription factors drive the specific gene expression patterns that define these identities, controlling almost every phenomenon in a cell from development to homeostasis. Therefore, transcription factors play an important role in generating and regulating behavior. Here, we describe the transcription factors, the pathways they regulate, and the neurons that drive chemosensation, mechanosensation, thermosensation, osmolarity sensing, complex, and sex-specific behaviors in the animal model Caenorhabditis elegans. We also discuss the current limitations in our knowledge, particularly our minimal understanding of how transcription factors contribute to the adaptive behavioral responses that are necessary for organismal survival.

Torpe N et al. (2019) Cell Rep "A Protein Disulfide Isomerase Controls Neuronal Migration through Regulation of Wnt Secretion."

Korswagen HC, Torpe N, Rella L, Gopal S, Baltaci O, Handley A, Pocock R

[

Cell Rep,

2019]

Appropriate Wnt morphogen secretion is required tocontrol animal development and homeostasis. Although correct Wnt globular structure is essential for secretion, proteins that directly mediate Wnt folding and maturation remain uncharacterized. Here, we report that protein disulfide isomerase-1 (PDI-1), a protein-folding catalyst and chaperone, controls secretion of the Caenorhabditis elegans Wnt ortholog EGL-20. We find that PDI-1 function is required to correctly form an anteroposterior EGL-20/Wnt gradient during embryonic development. Furthermore, PDI-1 performs this role in EGL-20/Wnt-producing epidermal cells to cell-non-autonomously control EGL-20/Wnt-dependent neuronal migration. Using pharmacological inhibition, we further show that PDI function is required in human cells for Wnt3a secretion, revealing a conserved role for disulfide isomerases. Together, these results demonstrate a critical role for PDIs within Wnt-producing cells to control long-range developmental events that are dependent on Wnt secretion.

Cornell R et al. (2024) Nat Commun "Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans."

Godini R, Harradine B, Cao W, Pocock R, Handley A, Cornell R

[

Nat Commun,

2024]

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.

Nehammer C et al. (2019) Elife "Interferon--induced miR-1 alleviates toxic protein accumulation by controlling autophagy."

Nehammer C, Rubinsztein DC, Gopal S, Ng L, Handley A, Ejlerskov P, Pocock R, Lee H, Moreira P, Issazadeh-Navikas S

[

Elife,

2019]

Appropriate regulation of autophagy is crucial for clearing toxic proteins from cells. Defective autophagy results in accumulation of toxic protein aggregates that detrimentally affect cellular function and organismal survival. Here, we report that the microRNA miR-1 regulates the autophagy pathway through conserved targeting of the orthologous Tre-2/Bub2/CDC16 (TBC) Rab GTPase-activating proteins TBC-7 and TBC1D15 in Caenorhabditis elegans and mammalian cells, respectively. Loss of miR-1 causes TBC-7/TBC1D15 overexpression, leading to a block on autophagy. Further, we found that the cytokine interferon-b (IFN-b) can induce miR-1 expression in mammalian cells, reducing TBC1D15 levels, and safeguarding against proteotoxic challenges. Therefore, this work provides a potential therapeutic strategy for protein aggregation disorders.

Gorelick S et al. (2019) Elife "PIE-scope, integrated cryo-correlative light and FIB/SEM microscopy."

Gervinskas G, Whisstock JC, Handley A, Johnson TK, Buckley G, Caggiano MP, de Marco A, Gorelick S, Pocock R

[

Elife,

2019]

Cryo-Electron Tomography (cryo-ET) is emerging as a revolutionary method for resolving the structure of macromolecular complexes in situ. However, sample preparation for in situ Cryo-ET is labour-intensive and can require both cryo-lamella preparation through cryo-Focused Ion Beam (FIB) milling and correlative light microscopy to ensure that the event of interest is present in the lamella. Here, we present an integrated cryo-FIB and light microscope setup called the Photon Ion Electron microscope (PIE-scope) that enables direct and rapid isolation of cellular regions containing protein complexes of interest. Specifically, we demonstrate the versatility of PIE-scope by preparing targeted cryo-lamellae from subcellular compartments of neurons from transgenic Caenorhabditis elegans and Drosophila melanogaster expressing fluorescent proteins. We designed PIE-scope to enable retrofitting of existing microscopes, which will increase the throughput and accuracy on projects requiring correlative microscopy to target protein complexes. This new approach will make cryo-correlative workflow safer and more accessible.

Baltaci O et al. (2022) iScience "Atypical TGF-β signaling controls neuronal guidance in Caenorhabditis elegans"

Snieckute G, Archer S, Cao W, Handley A, Sherry T, Haas M, Pocock R, Pedersen ME, Baltaci O

[

iScience,

2022]

Coordinated expression of cell adhesion and signaling molecules is crucial for brain development. Here, we report that the Caenorhabditis elegans transforming growth factor β (TGF-β) type I receptor SMA-6 (small-6) acts independently of its cognate TGF-β type II receptor DAF-4 (dauer formation-defective-4) to control neuronal guidance. SMA-6 directs neuronal development from the hypodermis through interactions with three, orphan, TGF-β ligands. Intracellular signaling downstream of SMA-6 limits expression of NLR-1, an essential Neurexin-like cell adhesion receptor, to enable neuronal guidance. Together, our data identify an atypical TGF-β-mediated regulatory mechanism to ensure correct neuronal development.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[

Sci Rep,

2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

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